EphA3 as a target for antibody immunotherapy in acute lymphoblastic leukemia

Charmsaz, Sara; Al-Ejeh, Fares; Yeadon, Trina; Miller, Kirrilee J; Smith, Florentia M.; Stringer, Brett W.; Moore, Andrew S.; Lee, F. T.; Cooper, Leanne; Stylianou, Con; Yarranton, G. T.; Woronicz, John; Scott, Andrew M.; Lackmann, Martin; Boyd, Andrew W.

doi:10.1038/leu.2016.371

Cited by 31 publications

(28 citation statements)

References 31 publications

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“…The conjugate cytotoxin of ephrinA5-Fc and PE38QQR potently and specifically killed glioblastoma tumor cells (12). The EPHA3-specific monoclonal antibody IIIA4 was also found to have antitumor effects in EPHA3-expressing leukemic xenografts (13). Accordingly, EPHA3 has been paid more attention as one of the promising targets for the treatment of several cancers (14,15).…”

Section: Androgen Receptor Induces Epha3 Expression By Interacting Wimentioning

confidence: 99%

Androgen receptor induces EPHA3 expression by interacting with transcription factor SP1

Xiao-wei

Chen

et al. 2018

Oncol Rep

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Erythropoietin‑producing hepatocellular carcinoma cell surface type‑A receptor 3 (EPHA3) has been found to promote the proliferation and survival of prostate cancer (PCa) cell lines and prostate tumor development in nude mice. However, the regulation of EPHA3 in PCa remains largely unknown. This study is aimed to investigate the association between EPHA3 expression and androgen receptor (AR) signaling and the potential mechanism. We determined mRNA and protein levels of EPHA3 and AR signaling‑related genes in the PCa cell line 22Rv1 by reverse transcription‑polymerase chain reaction (RT‑PCR) and western blotting, respectively. The EPHA3 mRNA and protein levels were both found to be elevated by dihydrotestosterone (DHT) hormone in a dose‑ and time‑dependent manner, as AR and prostate‑specific antigen (PSA) expression were increased. Similarly, EPHA3 protein levels were also increased in the PCa cell line LNCaP stimulated with DHT or mibolerone (Mib). Overexpression of pEGFP‑AR in 22Rv1 cells significantly increased the EphA3 level, while AR knockdown with small interfering RNA (siRNA) for AR (siAR) markedly decreased the expression of EPHA3. The key EPHA3 promoter region associated with AR regulation was evaluated by co‑transfection of various pGL3‑basic‑luciferase reporter plasmids, containing EPHA3 core promoter fragments differing in length, with the AR plasmid or siAR into 22Rv1 cells. AR overexpression in 22Rvl cells raised the EphA3 promoter transcription activity of pGL3‑EPHA3‑Luc (EPHA3‑Luc)‑789, and vice versa. Similarly, luciferase activity of EPHA3‑Luc‑317 was also clearly affected. However, truncated EPHA3‑Luc‑237 without the transcription factor specific protein 1 (SP1) binding sites or EPHA3‑Luc‑789ΔSP1 with modified SP1 binding sites clearly decreased EPHA3 promoter activity regardless of whether AR was overexpressed or blocked. Treatment of 22Rv1 cells with 10 and 100 nM of the SP1 inhibitor mithramycin A for 24 and 48 h significantly reduced EPHA3 mRNA and protein levels. Additionally, selective inhibition of SP1 with siRNA SP1 (siSP1) at various concentration from 25 to 75 nM, reduced the EPHA3 protein level in PCa LNCaP cells, accordingly. Co‑immunoprecipitation (co‑IP) and chromatin IP (ChIP) assays were performed to determine whether AR forms a transcription factor complex with Sp1 that binds the EPHA3 core promoter region to sense androgen induction. The result suggests that the interaction of AR and SP1 contributes to regulate EPHA3 expression, and the SP1 binding sites (‑295~‑261) in the EPHA3 core promoter region is crucial to the regulation of EPHA3 expression in response to androgen hormone stimuli.

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Section: Androgen Receptor Induces Epha3 Expression By Interacting Wimentioning

confidence: 99%

Androgen receptor induces EPHA3 expression by interacting with transcription factor SP1

Xiao-wei

Chen

et al. 2018

Oncol Rep

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“…Recent research efforts have focused on new cellular surface targets like CD27 44 and EphA3 61 , as well as improving cancer eradication though development of antibody drug conjugates for CD22 62 . Anti-CD22 antibody therapies have arguably been the most successful, and clinically translatable in treating ALL and other leukemias and lymphomas.…”

Section: Engineered Antibodies Enzymes and Antibody-drug Conjugamentioning

confidence: 99%

Drug discovery and therapeutic delivery for the treatment of B and T cell tumors

Stephenson

Singh

2017

Advanced Drug Delivery Reviews

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Hematological malignancies manifest as lymphoma, leukemia, and myeloma, and remain a burden on society. From initial therapy to endless relapse-related treatment, societal burden is felt not only in the context of healthcare cost, but also in the compromised quality of life of patients. Long-term therapeutic strategies have become the standard in keeping hematological malignancies at bay as these cancers develop resistance to each round of therapy with time. As a result, there is a continual need for the development of new drugs to combat resistant disease in order to prolong patient life, if not to produce a cure. This review aims to summarize advances in targeting lymphoma, leukemia, and myeloma in both cutting-edge and well established platforms. Current standard of treatment will be reviewed for these malignancies and emphasis will be made on new therapy development in the areas of antibody engineering, epigenetic small molecule inhibiting drugs, vaccine development, and chimeric antigen receptor cell engineering. In addition, platforms for the delivery of these and other drugs will be reviewed including antibody-drug conjugates, micro- and nanoparticles, and multimodal hydrogels. Lastly, we propose that tissue engineered constructs for hematological malignancies are the missing link in targeted drug discovery alongside mouse and patient-derived xenograft models.

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“…Many studies have showed expression of the Eph/ephrin family of proteins on malignant hematopoietic cells [28,29]. Human EphA3 was first identified in a pre-B-ALL cell line and was subsequently shown to be expressed in a proportion of both lymphoid and myeloid leukemias [28][29][30][31][32]. EphA3 is the first Eph receptor to have been investigated successfully in clinical trials in hematological cancers [32,33].…”

Section: Use Of Eph Receptors As Mab Therapy In Hematological Malignamentioning

confidence: 99%

Targeted therapies in hematological malignancies using therapeutic monoclonal antibodies against Eph family receptors

Charmsaz

Scott

Boyd

2017

Experimental Hematology

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The use of monoclonal antibodies (mAbs) and molecules derived from them has achieved considerable attention and success in recent years, establishing this mode of therapy as an important therapeutic strategy in many cancers, in particular hematological tumors. mAbs recognize cell surface antigens expressed on target cells and mediate their function through various mechanisms such as antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, or immune system modulation. The efficacy of mAb therapy can be improved when they are conjugated to a highly potent payloads, including cytotoxic drugs and radiolabeled isotopes. The Eph family of proteins has received considerable attention in recent years as therapeutic targets for treatment of both solid and hematological cancers. High expression of Eph receptors on cancer cells compared with low expression levels in normal adult tissues makes them an attractive candidate for cancer immunotherapy. In this review, we detail the modes of action of antibody-based therapies with a focus on the Eph family of proteins as potential targets for therapy in hematological malignancies.

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EphA3 as a target for antibody immunotherapy in acute lymphoblastic leukemia

Cited by 31 publications

References 31 publications

Androgen receptor induces EPHA3 expression by interacting with transcription factor SP1

Androgen receptor induces EPHA3 expression by interacting with transcription factor SP1

Drug discovery and therapeutic delivery for the treatment of B and T cell tumors

Targeted therapies in hematological malignancies using therapeutic monoclonal antibodies against Eph family receptors

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